Dissolution and disintegration of solid dosage forms such as multiple-layer tablet with different active ingredients depend on formulation and properties used in the formulations, and it may sometimes result in counterintuitive release kinetics. In this manuscript, we investigate the behavior of combined acetylsalicylic acid and mefenamic acid bi- and triple-layer formulations. We show that the simulation model with a cellular automata predicted the impact of the inert layer between the different active ingredients on each drug release and provide a good agreement with the experimental results. Also, it is shown that the analysis based on the Noyes-Whitney equation in combination with a cellular automata-supported dissolution and disintegration numerical solutions explain the nature of the unexpected effects. We conclude that the proposed simulation approach is valuable to predict the influence of material attributes and process parameters on drug release from multicomponent and multiple-layer pharmaceutical tablets and to help us develop the drug product formulation.
To elucidate the mechanisms of vitamin C transport across the blood-retinal barrier (BRB) in vivo and in vitro. METHODS. [(14)C]Dehydroascorbic acid (DHA) and [(14)C]ascorbic acid (AA) transport in the retina across the BRB were examined using in vivo integration plot analysis in rats, and the transport mechanism was characterized using a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB2) as an in vitro model of the inner BRB.The apparent influx permeability clearance (K(in)) per gram of retina of [(14)C]DHA and [(14)C]AA was found to be 2.44 x 10(3) microL/(min x g retina) and 65.4 microL/(min x g retina), respectively. In the retina and brain, the K(in) of [(14)C]DHA was approximately 38 times greater than that of [(14)C]AA, whereas there was no major difference in the heart. The K(in) of [(14)C]DHA in the retina was eight times greater than that in the brain. HPLC analysis revealed that most of the vitamin C accumulated in AA form in the retina. These results suggest that vitamin C is mainly transported in DHA form across the BRB and accumulates in AA form in the rat retina. In an in vitro uptake study in TR-iBRB2 cells, the initial uptake rate of [(14)C]DHA was 37 times greater than that of [(14)C]AA, which is in agreement with the results of the in vivo study. [(14)C]DHA uptake by TR-iBRB2 cells took place in an Na(+)-independent and concentration-dependent manner with a K(m) of 93.4 microM. This process was inhibited by substrates and inhibitors of glucose transporters. [(14)C]DHA uptake was inhibited by D-glucose in a concentration-dependent manner with a 50% inhibition concentration of 5.56 mM. Quantitative real-time PCR and immunostaining analyses revealed that expression of GLUT1 and -3 was greater than that of the Na(+)-dependent L-ascorbic acid transporter (SVCT)-2 in TR-iBRB2 cells.Vitamin C is mainly transported across the BRB as DHA mediated through facilitative glucose transporters and accumulates as AA in the rat retina.
Vitamin C is mainly transported across the blood–retinal and –brain barriers as dehydroascorbic acid (DHA) via a facilitative glucose transporter, GLUT1, and accumulates as ascorbic acid in the retina and brain. To investigate whether DHA transport to the retina and brain is changed by hyperglycemia, [14C]DHA transport across the blood–retinal and –brain barriers was examined using in vivo integration plot analysis in streptozotocin-induced diabetic rats with a 3-week duration of diabetes and in normal rats. Blood-to-retina and -brain transport of [14C]DHA was reduced by 65.5% and 84.1%, respectively, in diabetic rats compared with normal rats, whereas there was no major difference in the heart. Therefore, we propose that hyperglycemia reduces the supply of vitamin C to the retina and brain.
Putrescine is a bioactive polyamine. Its retinal concentration is strictly controlled to maintain a healthy sense of vision. The present study investigated putrescine transport at the blood-retinal barrier (BRB) to gain a better understanding of the mechanisms of putrescine regulation in the retina. Our microdialysis study showed that the elimination rate constant during the terminal phase was significantly greater (1.90-fold) than that of [14C]D-mannitol, which is a bulk flow marker. The difference in the apparent elimination rate constants of [3H]putrescine and [14C]D-mannitol was significantly decreased by unlabeled putrescine and spermine, suggesting active putrescine transport from the retina to the blood across the BRB. Our study using model cell lines of the inner and outer BRB showed that [3H]putrescine transport was time-, temperature-, and concentration-dependent, suggesting the involvement of carrier-mediated processes in putrescine transport at the inner and outer BRB. [3H]Putrescine transport was significantly reduced under Na+-free, Cl--free, and K+-replacement conditions, and attenuated by polyamines or organic cations such as choline, a choline transporter-like protein (CTL) substrate. Rat CTL1 cRNA-injected oocytes exhibited marked alterations in [3H]putrescine uptake, and CTL1 knockdown significantly reduced [3H]putrescine uptake in model cell lines, suggesting the possible participation of CTL1 in putrescine transport at the BRB.
Abstract : The brain efflux index method has been used to clarify the mechanism of efflux transport of acidic amino acids such as L‐aspartic acid (L‐Asp), L‐glutamic acid (L‐Glu), and D‐aspartic acid (D‐Asp) across the blood‐brain barrier (BBB). About 85% of L‐[ 3 H]Asp and 40% of L‐[ 3 H]Glu was eliminated from the ipsilateral cerebrum within, respectively, 10 and 20 min of microinjection into the brain. The efflux rate constant of L‐[ 3 H]Asp and L‐[ 3 H]Glu was 0.207 and 0.0346 min ‐1 , respectively. However, D‐[ 3 H]Asp was not eliminated from brain over a 20‐min period. The efflux of L‐[ 3 H]Asp and L‐[ 3 H]Glu was inhibited in the presence of excess unlabeled L‐Asp and L‐Glu, whereas D‐Asp did not inhibit either form of efflux transport. Aspartic acid efflux across the BBB appears to be stereospecific. Using a combination of TLC and the bioimaging analysis, attempts were made to detect the metabolities of L‐[ 3 H]Asp and L‐[ 3 H]Glu in the ipsilateral cerebrum and jugular vein plasma following a microinjection into parietal cortex, area 2. Significant amounts of intact L‐[ 3 H]Asp and L‐[ 3 H]Glu were found in all samples examined, including jugular vein plasma, providing direct evidence that at least a part of the L‐Asp and L‐Glu in the brain interstitial fluid is transported across the BBB in the intact form. To compare the transport of acidic amino acids using brain parenchymal cells, brain slice uptake studies were performed. Although the slice‐to‐medium ratio of D‐[ 3 H]Asp was the highest, followed by L‐[ 3 H]Glu and L‐[ 3 H]Asp, the initial uptake rate did not differ for both L‐[ 3 H]Asp and D‐[ 3 H]Asp, suggesting that the uptake of aspartic acid in brain parenchymal cells is not stereospecific. These results provide evidence that the BBB may act as an efflux pump for L‐Asp and L‐Glu to reduce the brain interstitial fluid concentration and act as a static wall for D‐Asp.
Abstract In contrast to the corresponding reaction of β‐hydroxy esters or sulfoxides, the alkylation of dianions generated from the title compounds (I) and (VI) yields the sterically more crowded erythro isomers as major products.
